PROJECT SUMMARY Deep brain stimulation (DBS) has had great impact, helping patients with disorders such as Parkinson's disease and obsessive?compulsive disorder (OCD), and with great potential for other disorders such as depression and Alzheimer's disease. DBS, being a surgical procedure, bears the potential for complications that limit its deployment and adoption. Transient non-invasive brain stimulation methods, such as transcranial magnetic stimulation (TMS) and transcranial current stimulation (tCS), also show therapeutic potential and have been used in many human clinical and neuroscientific investigations, but they fail to achieve focality at depth. In a paper we recently published in Cell, we reported the initial stages of development of a non-invasive, steerable, 3D focal brain stimulation method that has the potential in the future to transform the risk-benefit ratio for DBS by providing an alternative without the need for surgery, as well as to improve the precision of other non-invasive methods such as TMS or tCS. We showed that by delivering two electric fields at slightly different carrier frequencies, which are themselves too high to recruit effective neural firing but for which the offset frequency is low enough to drive neural activity, we can create an electric field envelope at the offset frequency. We found that this low-frequency modulated electric field can cause neurons to be electrically activated at a deep focus, without driving neighboring, or overlying, brain regions. We now propose to refine this technology for multiple clinically relevant targets and collaboratively deploy them into several relevant settings, including the demonstration of early human translation assessing feasibility, safety, steerability, and depth selectivity. Specifically, we will (Aim 1) optimize TI stimulation for three targets of clinical interest, basal forebrain, central thalamus, and visual cortex, for investigation in humans and mice; (Aim 2) translate TI stimulation to human and demonstrate safety, steerable precision, and depth selectivity; (Aim 3) develop TI implementations of anesthesia, in rodent models. In this way we will deliver to the clinical community a technology ready for clinical trials in a diversity of clinical contexts.